Highly efficient conversion of benzoates to alcohols with sodium borohydride in DME-MeOH

Article abstract of DOI:10.1055/s-1999-2918

Methoxybenzoates were quantitatively reduced to the corresponding alcohols with sodium borohydride in a mixed solvent (DME-MeOH). The described method was applicable to a large scale synthesis.

Full text of DOI:10.1055/s-1999-2918

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LETTER
Highly Efficient Conversion of Benzoates to Alcohols with Sodium
Borohydride in DME-MeOH
Atsuhiko Zanka,* Hiroki Ohmori, Takumi Okamoto
Technological Development Laboratories, Fujisawa Pharmaceutical Co. Ltd., 2-1-6 Kashima, Yodogawa-ku,
Osaka, 532-8514, Japan
Fax +81 6 6390 1183; E-mail: atsuhiko_zanka@po.fujisawa.co.jp
Received 21 July 1999
As pointed out in a previous paper, the reactivity is deeply
affected by the solvent used.10 Thus, we firstly evaluated
several mixed solvent systems at a temperature of 50°C
with a view to developing an improved reduction system.
As can be seen from Table 1, best results were obtained
by using DME (dimethoxyethane)-MeOH or DGM (di-
glyme)-MeOH as solvent. From the standpoint of efficient
isolation of 1b on large scale, DME (bp 85°C) is more fa-
vorable than DGM (bp 162°C), since it is easer to remove.
Abstract: Methoxybenzoates were quantitatively reduced to the
corresponding alcohols with sodium borohydride in a mixed solvent
(DME-MeOH). The described method was applicable to a large
scale synthesis.
Key words: sodium borohydride, ester, benzoate, alcohol, reduc-
tion
Recently, it became necessary to prepare 3-methoxy-4-
methylbenzylalcohol (1b) in large quantities. Although
various synthetic procedures for methoxy-benzylalcohols
are known in the literature1, there are few practical meth-
ods that are amenable to a large scale synthesis. The con-
ceptually simple way to 1b uses the reduction of 3-
methoxy-4-methylbenzoate (1a) which is achieved with
LiAlH4 as the most common reductant on a laboratory
scale.1a,b However, LiAlH4 involves several drawbacks
from the standpoint of large scale manufacturability. For
example, it presents significant pyrophoric hazards and
involves large amounts of generated wastes. In addition,
significant amounts of material are often absorbed on the
surface of the insoluble materials in the reaction, making
the workup procedure tedious. As an alternative reagent,
NaBH4 is especially attractive since this reagent is inex-
pensive and readily available in large quantities. Although
OMe
OMe
H3C
NaBH4
H3C
OMe
OH
O
Scheme
2
esters are essentially inert to NaBH4 except for those con-
taining participating neighboring groups,3 the reduction
reaction has been achieved by addition of reagents which
enhance the reduction power. For example, Santaniello et
al. reported a novel reduction of benzoates in polyethyl-
ene glycol under mild conditions.4 Though the method is
efficient enough to give materials in gram quantities, con-
trol of evolution of hydrogen gas during heating the reac-
tion mixture is problematic on a large scale. The reduction
of esters into the corresponding alcohols was performed in
the presence of metals such as LiBr5 or AlCl3,6 a large
amount of ethanedithiol (10 equiv)7 or with a large excess
of NaBH4 (20 equiv) in MeOH.8 More conveniently, the
same reactions are possible with NaBH4 in THF-MeOH or
tert-BuOH-MeOH as a mixed solvent, as reported by Soai
et al.9 However, when directly applying this method, sig-
nificant starting material remained unreacted in the case
of methoxybenzoates, presumably due to an electron do-
nating effect reducing the reactivity of the ester group.
Herein, we wish to report a modified procedure for quan-
titatively converting methoxy-benzoates to the corre-
sponding alcohols in a rapid manner.
Next, we investigated the optimized reaction conditions in
DME-MeOH allowing complete starting material con-
sumption and found that a higher reaction temperature in
the presence of excess amounts of NaBH4 was crucial for
good conversion (Table 2). The reaction was also slightly
improved by having the time of addition of methanol into
the reaction mixture prolonged (entry 5, 6). As a result of
these findings, 1a was quantitatively reduced. Extractive
workup followed by concentration provided 1b in excel-
lent yield and quality.
Finally, we have extended this method to the reduction of
several methoxybenzoates.11 As shown in Table 3, the
DME-MeOH method has advantages over the THF-
Synlett 1999, No. 10, 1636–1638 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Highly Efficient Conversion of Benzoates to Alcohols with Sodium Borohydride in DME-MeOH
1637
MeOH method,9 allowing complete consumption of start-
ing material. Based on these optimized reaction condi-
tions, o-methoxy- and m-methoxybenzoate were
quantitatively reduced to the corresponding alcohols (en-
try 4, 6). On the other hand, methyl p-methoxybenzoate
required somewhat harsher conditions presumably due to
the stronger electron donating effect of the para methoxy
group. This problem was overcome by further slow addi-
tion of methanol into the reaction mixture (entry 9). In
agreement with results in previous reports,4,7 p-hydroxy-
benzoate was not reduced to any significant degree by
changing reaction conditions (entry 14).
In summary, we could demonstrate a new method for
quantitative reduction of methoxybenzoates into the cor-
responding alcohols. Slow addition of methanol in the
presence of an optimized amount of NaBH4 in DME as
solvent, maintaining the reaction mixture at reflux, led to
a significant improvement in the yield and is crucial to
success. This procedure should expand the range of alco-
hols accessible from benzoates with NaBH4. The de-
scribed methods were successfully scaled up in a pilot
plant to give >27 Kg of 1b.
Acknowledgement
We especially thank Dr. David Barrett, Medicinal Chemistry Re-
search Laboratories, Fujisawa Pharmaceutical Co. Ltd., for his in-
terest and on-going advice on this work.
References and Notes
(1) (a) Irie, H.; Matsumoto, R.; Nishimura, M.; Zhang, Y. Chem.
Pharm. Bull. 1990, 38, 1852. (b) Majetich, G.; Hicks, R.;
Zhang, Y.; Tian, X.; Feltman, T. L.; Fang, J.; Duncan, S. Jr. J.
Org. Chem. 1996, 61, 8169. (c) Quelet, R.; Allard, J.; Ducasse,
J.; Germain, Y. Bull. Soc. Chim. Fr. 1937, 4, 1092. (d)
Kametani, T.; Kigawa, Y.; Nemoto, H.; Ihara, M.; Fukumoto,
K. J. Chem. Soc., Perkin 1. 1980, 1607.
(2) Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979, 35, 567.
(3) Barnett, J. E. G.; Kent, P. W. J. Chem. Soc. 1963, 2743.
(4) Santaniello, E.; Ferraboschi, P.; Sozzani, P. J. Org. Chem.
1981, 46, 4584.
(5) Brown, H. C.; Edward, J. M.; Rao, B. C. S. J. Am. Chem. Soc.
1955, 77, 6209.
(6) Brown, H. C.; Rao, B. C. S. J. Am. Chem. Soc. 1956, 78, 2582.
(7) Maki, Y.; Kikuchi, K.; Sugiyama, H.; Seto, S. Tetrahedron
Lett. 1975, 3295.
(8) Brown, M. S.; Rapoport, H. J. Org. Chem. 1963, 28, 3261.
(9) (a) Soai, K.; Oyamada, H.; Takase, M.; Ookawa, A. Bull.
Chem. Soc. Jpn. 1984, 57, 1948. (b) Soai, K.; Oyamada, H.;
Ookawa, A. Synth. Commun. 1982, 12, 463.
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A. Zanka et al.
LETTER
(10) Krishnamurthy, S. J. Org. Chem. 1980, 45, 2550.
(11) General procedure for conversion of benzoates to alcohols.
To a mixture of methyl methoxybenzoate (14 mmol) and
NaBH4 (2.65 g, 70 mmol) in DME (25 mL) was added MeOH
(12.5 mL) dropwise over a period of 1 h maintaining the
temperature of >70°C. After stirring for an additional 1 h, the
reaction mixture was quenched with water and extracted with
toluene. The separated aqueous layer was reextracted with
toluene. The combined organic layers were washed
(12) 4-methyl-3-methoxybenzylalcohol (1b);1H NMR (200 MHz,
CDCl3) δ = 2.20 (s, 3H), 3.81 (s, 3H), 4.60 (s, 2H), 6.80 (d, 2H,
J=7.7), 6.82 (s, 1H), 7.08 (d, 1H, J=7.3); IR (neat) 3400, 1259
cm-1 ; MS (EI) m/z 153 (M+H)+.
Article Identifier:
1437-2096,E;1999,0,10,1636,1638,ftx,en;Y15999ST.pdf
successively with water and 10% brine. Removal of the
solvent under reduced pressure gave product as a colorless
liquid which was homogeneous by HPLC analysis.
Synlett 1999, No. 10, 1636–1638 ISSN 0936-5214 © Thieme Stuttgart · New York